P580: CHARACTERISTICS AND OUTCOMES OF PATIENTS WITH WT1 MUTATED MYELOID NEOPLASMS: MAYO CLINIC EXPERIENCE
Authors: Rami Basmaci, Anmol Baranwal, Rong He, David Viswanatha, Patricia Greipp, James M Foran, Cecilia Arana Yi, Mithun Shah, Abhishek Mangaonkar, Mark Litzow, William Hogan, Kebede Benga, Antoine Saliba, Naseema Gangat, Ayalew Tefferi, Mrinal Patnaik, Aref Al-Kali, Hassan Alkhateeb
Journal: HemaSphere (2023)

Background: The Wilms’ Tumor 1 (WT1) is a tumor suppressor gene located on chromosome 11p13. WT1 mutations (m) have been documented in myeloid neoplasms, However, the impact of WT1 on characteristics and treatment outcomes of patients with WT1m across the spectrum of myeloid neoplasms (MN) has been rarely studied. Aims: Describe the genomic landscape of WT1 mutations in myeloid neoplasms, patients’ clinical outcomes and prognostics of survival. Methods: After IRB approval, patients with pathogenic WT1m were identified. Risk stratification of AML patients was done using European Leukemia Network 2022 (ELN 2022). Kaplan-Meier and log-rank methods were used to evaluate overall survival (OS). Cox-proportional hazard was used for multivariate analysis (MVA) for OS, and was calculated from time of WT1m acquisition. Only Variables with P < 0.1 were included. Variables with less than 10% incidence were excluded from MVA. Results: Seventy-five patients (44, 59% males) were found to have WT1 mutations. Median age at diagnosis was 60 years (range 18-83). AML was the predominant diagnosis (73.5%), followed by MDS (9.5%), MPAL (8%), CMML (4%), MPN (4%) and ALL (1%). Among AML patients, 24 (44%) had adverse, 25 (45%) intermediate and 6 (11%) favorable-risk stratified by ELN 2022 criteria. Thirty patients (55%) had abnormal cytogenetics, while only eight (15%) had complex karyotype. Secondary, and therapy related AML, were identified in three (5%) and four (7%) patients, respectively. Compared to WT1m AML, WT1m MPAL patients were two decades older (median of 56 vs 73 yrs, p=.02). B-cell lineage was the most common lymphoid lineage; as four were B/Myeloid (67%), one T/Myeloid (17%) and one AUL favoring B lineage (17%). Fifty-five patients (73%) had WT1m in the Zn-finger domain, there were (45%) codon 312-314, (23%) codon 301-303 and (13%) codon 394-396 mutations, representing mutational “hotspots”. Only codon 394-396 mutations were seen significantly more in MPAL compared to AML (50% vs 9%, p=.02). Frameshift mutations were the most common (63%) followed by nonsense (17%) and missense (12%) mutations. Twenty-four patients (32%) had multiple WT1 mutations, and the median number of WT1 mutations was 1 (range 1-4) and 2 (range 1-4) in AML and MPAL, respectively (p=.03). The median number of co-mutations was 2 (range 0-6). The most common were FLT3 (37%), RUNX1 (21%), NPM1 (17%) and ASXL1 (15%). Eleven patients (15%) had isolated WT1 mutation. Median overall survival (OS) for WT1m MN was 11.6 months (range 0 - 63) (number of deaths=59) There was no difference in survival between types of MN (p=.4). In univariate analysis, Age > 60, disease status at time of WT1m (newly diagnosed vs relapsed/refractory (R/R) disease), complex and monosomal karyotype, TP53, ASXL1, and KIT Asp816Val mutations were associated with worse OS, while FLT3m, CEBPA and allogenic stem cell transplant (allo-HSCT) were found to improve OS (33 (44%) patients received allo-HSCT). Only complex karyotype (HR=2.5, 95% CI (1.03 – 6.3), p=.04) and R/R disease at time of WT1m (HR=4.0, 95% CI (1.6 – 9.7), p=.002) remained significant in MVA while HSCT lost its significance in improving OS (HR=.4, 95% CI (0.1 – 1.1), p=.08). Summary/Conclusion: Among WT1m MN, we found that WT1m MPAL is associated with advanced age, multi-hit WT1m, and enrichment in codon 394-396 mutations, as compared to WT1m AML. In WT1m MN, only complex karyotype and R/R disease at WT1m emergence were associated with worse OS. Keywords: Acute myeloid leukemia, Myeloid malignancies, WT1, Mixed lineage leukemia